Elsevier

The Lancet

Volume 356, Issue 9246, 9 December 2000, Pages 1955-1964
The Lancet

Articles
Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials*

https://doi.org/10.1016/S0140-6736(00)03307-9Get rights and content

Summary

Background

This programme of overviews of randomised trials was established to investigate the effects of angiotensin-converting-enzyme (ACE) inhibitors, calcium antagonists, and other blood-pressure-lowering drugs on mortality and major cardiovascular morbidity in several populations of patients. We did separate overviews of trials comparing active treatment regimens with placebo, trials comparing more intensive and less intensive blood-pressure-lowering strategies, and trials comparing treatment regimens based on different drug classes.

Methods

The hypotheses to be investigated, the trials to be included, and the outcomes to be studied were all selected before the results of any participating trial were known. Individual participant data or group tabular data were provided by each trial and combined by standard statistical techniques.

Findings

The overview of placebo-controlled trials of ACE inhibitors (four trials, 12 124 patients mostly with coronary heart disease) revealed reductions in stroke (30% [95% Cl 15–43]), coronary heart disease (20% [11–28]), and major cardiovascular events (21% [14–27]). The overview of placebo-controlled trials of calcium antagonists (two trials, 5520 patients mostly with hypertension) showed reductions in stroke (39% [15–56]) and major cardiovascular events (28% [13–41]). In the overview of trials comparing blood-pressure-lowering strategies of different intensity (three trials, 20 408 patients with hypertension), there were reduced risks of stroke (20% [2–35]), coronary heart disease (19% [2–33]), and major cardiovascular events (15% [4–24]) with more intensive therapy. In the overviews comparing different antihypertensive regimens (eight trials, 37 872 patients with hypertension), several differences in cause-specific effects were seen between calcium-antagonist-based therapy and other regimens, but each was of borderline significance.

Interpretation

Strong evidence of benefits of ACE inhibitors and calcium antagonists is provided by the overviews of placebo-controlled trials. There is weaker evidence of differences between treatment regimens of differing intensities and of differences between treatment regimens based on different drug classes. Data from continuing trials of blood-pressure-lowering drugs will substantially increase the evidence available about any real differences that might exist between regimens.

Introduction

By the mid 1990s, evidence about the effects of blood-pressure-lowering regimens based mainly on diuretics and β-blockers was available from a series of randomised controlled trials involving a total of more than 47 000 hypertensive patients.1, 2, 3, 4, 5 Systematic overviews (or meta-analyses) of these trials showed that reductions in blood pressure of about 10–12 mm Hg systolic and 5–6 mm Hg diastolic conferred relative reductions in stroke risk of 38% and in risk of coronary heart disease of 16% within just a few years of beginning treatment.2, 3 The sizes of these effects were broadly consistent with those predicted from observational studies of the long-term associations of blood pressure with risk of stroke and coronary heart disease.6, 7, 8 Additionally, the sizes of these effects were similar in various major subgroups of trials and patients, and seemed to be largely independent of differences in disease event rates among patients assigned control. The few studies that directly compared the effects of diuretics and β-blockers detected no clear differences in risk of stroke or coronary heart disease.9, 10, 11, 12 Similarly, the few studies that had directly compared newer agents such as angiotensin-converting-enzyme (ACE) inhibitors and calcium antagonists with diuretics or β-blockers also failed to detect any clear differences.13, 14, 15, 16 However, these studies were individually and collectively too small to detect any plausibly modest differences (eg, 10–15% differences in relative risk) in the cause-specific effects of the regimens compared.

In addition to this evidence from patients with high blood pressure, other relevant evidence was available at that time from trials of several of the same agents in other groups of patients. Overviews of randomised controlled trials of β-blockers among patients with coronary disease had shown reductions of about a fifth in the risk of reinfarction or death.17 Overviews of trials of ACE inhibitors among patients with heart failure or left-ventricular dysfunction showed reductions of between a quarter and a fifth in the risks of death, myocardial infarction, or hospital admission for heart failure,18, 19 but few data were available about the effects of these agents among patients with preserved left-ventricular function. An overview of trials of ACE inhibitors among patients with acute myocardial infarction also showed relative reductions of about 7% in the risk of death.20 Overviews of trials of calcium antagonists among patients with coronary heart disease21, 22 had provided some evidence suggestive of increased mortality with dihydropyridine agents (mainly short-acting nifedipine) and reduced mortality with non-dihydropyridine agents (diltiazem and verapamil), but the available data were too few to provide reliable evidence about any such separate effects or, indeed, any overall effect of calcium antagonists.23

Over the past 5 years, a new series of trials has been completed, and several other trials started in efforts to further elucidate the effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs on mortality and major cardiovascular morbidity in several populations of patients including those with hypertension, diabetes mellitus, coronary heart disease, or renal disease. Before the results of any of these new trials were known, some studies were recognised as being too small individually to detect moderate, though potentially important, cause-specific effects of treatments or differences between treatment effects. Therefore, in July, 1995, the principal investigators from all of the large-scale trials that were in progress or in advanced stages of planning met and agreed to collaborate in a programme of prospectively planned overviews in which treatment effects and treatment differences would be estimated from the combined results of individual studies.24 Separate overviews were planned for trials that compared active treatment regimens with placebo, those that compared more intensive with less intensive blood-pressure-lowering strategies, and trials that assessed treatment regimens based on different drug classes. Estimates of treatment effects and treatment differences from these overviews should be subject to less random error than those from any one constituent trial, since they would be based on larger numbers of cause-specific outcomes.25 Additionally, by prospectively defining the studies to be included, the hypotheses to be addressed, and the outcomes to be studied, the estimates from these overviews might be less subject to bias than those from other overviews in which the studies, hypotheses, and outcomes are selected retrospectively with full knowledge of the individual study results.25 This report provides results from the first prospectively planned cycle of analyses by this collaborative group under the aegis of the WHO-International Society of Hypertension Liaison Committee.

Section snippets

Trial eligibility

The criteria for selection of trials for inclusion in these overviews were prespecified in the protocol for this project.24 Trials were eligible for inclusion if they met one of the following criteria: (1) randomisation of patients between a blood-pressure-lowering drug and placebo or other inactive control (irrespective of whether the intent of study treatment was to lower blood pressure and irrespective of whether patients were selected on the basis of high blood pressure); (2) randomisation

Characteristics of trials and patients included

Outcome data were available from 15 studies28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 that collectively included 74 696 individuals (table 1). The mean age of all participants was 62 years and 53% were male. Six studies provided outcome data from comparisons of an active agent with a placebo (five of which were among patients with cardiovascular disease or diabetes mellitus); three provided outcome data from comparisons of blood-pressure-lowering regimens of different

Discussion

The results of the first cycle of analyses from this programme of prospectively designed overviews show that benefits of blood-pressure-lowering drugs are not limited to regimens based on diuretics or β-blockers. The overview of placebo-controlled trials of ACE inhibitors shows that, with only a modest reduction in blood pressure, these agents decreased the risks of stroke, coronary heart disease, and major cardiovascular events by 20–30% among high-risk patients selected on the basis of a

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